Carlos L. Simmerling

Center for Structural Biology, Stony Brook University

The introduction of HIV-1 protease (HIV-PR) inhibitors has led to a dramatic increase in patient survival; however, these gains are threatened by the emergence of multi-drug-resistant strains. Design of inhibitors that overcome resistance would be greatly facilitated by deeper insight into the mechanistic events associated with binding of substrates and inhibitors. This seminar will describe the development of all-atom simulation methods and their application to HIV-PR. In these simulations, HIV-PR is observed to spontaneously interconvert between the experimentally determined conformations of HIV-PR upon addition or removal of an inhibitor. In addition, the simulations sample transient opening events in which the active site becomes accessible to incoming substrate or inhibitors. The simulations provide insight into the dynamic nature of inhibitor binding and how it is affected by mutations that result in drug resistance.